Process to chloroketones using oxazolines

ABSTRACT

This invention relates to a process for the preparation of an α-chloroketone compound comprising the steps of 
     (i) cyclizing an alkynyl amide to form a 5-methyleneoxazoline ##STR1## (ii) chlorinating the 5-methyleneoxazoline using trichloroisocyanuric acid to produce a chlorinated oxazoline intermediate ##STR2## and (iii) hydrolyzing the chlorinated oxazoline intermediate with an aqueous acid to produce the desired monochloroketone ##STR3## wherein Z is alkyl or substituted alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl or phenylene, 
     R is a hydrogen atom or alkyl and 
     R 1  and R 2  are each independently an alkyl or substituted alkyl group, or R 1  and R 2  together with the carbon atom to which they are attached form a cyclic structure. 
     Additionally, when R is a hydrogen atom, a dichloroketone can be conveniently formed through adjustment of reaction conditions.

This is a divisional of Ser. No. 09/058,832 filed Apr. 13, 1998, nowU.S. Pat. No. 5,859,254, which claims for domestic priority 60/043,555filed Apr. 15, 1997 under 119(e).

This invention relates to a novel, inexpensive process to prepare5-methyleneoxazolines from substituted alkynyl amides followed by thesubsequent conversion of the 5-methyleneoxazoline to an α-chloroketoneusing a convenient chlorinating agent followed by hydrolysis. Theresulting (α-chloroketones are useful as fungicides.

There are several problems in the existing field which the presentinvention successfully overcomes. Previously disclosed routes to thedesired 5-methyleneoxazoline from substituted alkynyl amides requiredthe use of strong and, consequently, expensive bases such as sodiumhydride or sodium amide. These bases require the use of scrupulouslyanhydrous conditions and are difficult to handle. Additionally, yieldsof the 5-methyleneoxazoline from the alkynyl amide are unacceptably lowfor economic viability. Other disclosed routes to the desired5-methyleneoxazoline from substituted alkynyl amides involve treatmentof the amide with silver ion in N,N-dimethylformamide. This type ofprocedure uses an expensive and environmentally toxic catalyst and asolvent that requires a difficult work-up and produces large volumes oforganic laden aqueous waste. Still other disclosed routes employ watersoluble solvents in a method to form a 5-methyleneoxazoline, but suchsolvents are difficult to efficiently recover and result in a processpossessing undesirable cost.

The subsequent preparation of an α-chloroketone from the resulting5-methyleneoxazoline by the known and usual methods, such as by usingchlorine gas or N-chlorosuccinimide as the chlorinating agent, is alsoproblematic because of a lack of selectivity for monochlorination; bothunderchlorinated and overchlorinated ketones are typically formed inaddition to the desired monochloroketone after hydrolysis of the5-chloromethylene oxazoline. Furthermore, the use of chlorine presentshazards and an equipment expense well known to those skilled in the art.

We have discovered two convenient routes to 5-methyleneoxazolines fromsubstituted alkynyl amides. The first requires only the use of aninexpensive base such as an aqueous solution of sodium hydroxide orsodium carbonate in the presence of an organic solvent and a phasetransfer agent (PTA). The second requires only the use of an inexpensiveorganic or mineral acid such as oleum, an organosulfonic acid or atrihaloacetic acid in the presence of an organic solvent. Furthermore,we have identified a novel chlorination reagent, trichloroisocyanuricacid (TCIA), which chlorinates the resulting 5-methyleneoxazolineselectively to give a monochlorinated intermediate which, uponacid-catalyzed hydrolysis, affords the desired α-monochloroketoneselectively and in high yield. TCIA is a high melting, easily handleablesolid which can be utilized in extremely precise amounts in order toavoid under- or over- chlorination of the desired material. AlthoughTCIA is a well known, inexpensive and commercially available compoundused in the chlorination of swimming pool water and the disinfection ofdrinking water, its use as a convenient and selective chlorination agentfor 5-methyleneoxazolines had not been disclosed before this time. Anadditional feature of this invention provides a convenient process forthe selective formation of α,α-dichloroketones which are also useful asfungicides.

WO 95/19351 discloses the formation of aryl-5-methyleneoxazolederivatives by cyclization of an alkynyl amide in the presence of abase. However, only the use of a large amount of strong base for thecyclization is exemplified. Moreover, the use of a phase transfer agentto ameliorate the cyclization is not suggested. The use of an acid forthe cyclization is also not suggested. Yih et al. in Weed Science, 18,604-607 (1970) and in J.Agr. Food Chem., 19, 314-317 (1971) disclose theformation of an aryl-5-methyleneoxazoline from a substituted alkynylamide using acid, base or silver ion in an aqueous alcohol solutionfollowed by hydrolysis to a ketone not possessing an α-chloro group.U.S. Pat. Nos. 4,822,902 and 5,304,572 disclose the formation of5-(chloromethylene)oxazolines which are obtained by treating an alkynylamide with chlorine. However, the use of TCIA as a chlorinating agent isnot disclosed or suggested. These references, either by themselves ortaken together, do not suggest the process of the present invention.

One embodiment of this invention provides a convenient process toα-chloroketories, which are useful as fungicides, comprising the stepsof cyclizing a substituted alkynyl amide using a mild aqueous base inthe presence of an organic solvent and a phase transfer agent to form a5-methyleneoxazoline in a first step, chlorinating the5-methyleneoxazoline in a solvent using trichloroisocyanuric acid toproduce a chlorinated oxazoline intermediate in a second step, andsubsequently hydrolyzing the chlorinated oxazoline intermediate with anaqueous acid to produce the desired monochloroketone in a third step.The ketone is typically isolated by a crystallization-filtrationprocedure.

Specifically, this embodiment provides a process for the preparation ofan α-chloroketone compound of formula (I) comprising the steps of

(i) cyclizing an alkynyl amide of formula (II) using a mild aqueous basein the presence of an organic solvent and a phase transfer agent (PTA)to form a 5-methyleneoxazoline of formula (III) ##STR4##

(ii) chlorinating the 5-methyleneoxazoline of formula (III) in a solventusing trichloroisocyanuric acid to produce a chlorinated oxazolineintermediate of formula (IV) ##STR5## and

(iii) hydrolyzing the chlorinated oxazoline intermediate of formula (IV)with an aqueous acid to produce the desired monochloroketone of formula(I) ##STR6## wherein

Z is alkyl or substituted alkyl, aryl or substituted aryl, heteroaryl orsubstituted heteroaryl or phenylene,

R is a hydrogen atom or alkyl, and

R¹ and R² are each independently an alkyl or substituted alkyl group, orR¹ and R² together with the carbon atom to which they are attached forma cyclic structure.

In a preferred form of this embodiment,

Z is (C₁ -C₈)alkyl, phenyl or phenyl substituted with up to threesubstituents independently selected from the group consisting of halo,(C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₂ -C₆)alkynyl, nitro and cyano,2-naphthyl, 3-pyridyl and 1,4-phenylene,

R is a hydrogen atom or a (C₁ -C₄)alkyl, and

R¹ and R² are each independently a (C₁ -C₄)alkyl or R¹ and R² togetherwith the carbon atom to which they are attached form a cyclopentyl orcyclohexyl ring.

In a more preferred form of this embodiment,

Z is 3-heptyl, phenyl, 4-halophenyl, 2,6-dihalophenyl, 4-(C₁-C₄)alkylphenyl, 3,5-dihalophenyl, 3,5-di(C₁ -C4)alkylphenyl, 4-(C₁-C₄)alkyl-3,5-dihalophenyl, 4-cyano-3,5-dihalophenyl, 4-(C₁-C₄)alkoxy-3,5-dihalophenyl, 4-nitrophenyl, 2-naphthyl, 3-pyridyl or1,4-phenylene,

R is a hydrogen atom, methyl or ethyl, and

R¹ and R² are each independently methyl or ethyl or R¹ and R² togetherwith the carbon atom to which they are attached form a cyclohexyl ring.

In an even more preferred form of this embodiment,

Z is 4-chlorophenyl, 2,6-difluorophenyl, 3,5-dimethylplhenyl,3,5-dichloro-4-methylphenyl, 4-nitrophenyl, 1,4-phenylene, 2-naphthyl,3-pyridyl or 3-heptyl,

R is a hydrogen atom, and

R¹ and R² are each independently methyl or ethyl.

A second embodiment of this invention provides a convenient process toα-chloroketones, which are useful as fungicides, comprising the steps ofcyclizing an alkynyl amide using an acid in the presence of an organicsolvent under anhydrous conditions to form a 5-methyleneoxazoline in afirst step, chlorinating the 5-methyleneoxazoline in a solvent usingtrichloroisocyanuric acid to produce a chlorinated oxazolineintermediate in a second step, and subsequently hydrolyzing thechlorinated oxazoline intermediate with an aqueous acid to produce thedesired monochloroketone in a third step. The ketone is typicallyisolated by a crystallization-filtration procedure.

Specifically, this embodiment provides a process for the preparation ofan α-chloroketone compound of formula (I) comprising the steps of

(i) cyclizing an alkynyl amide of formula (II) using an acid to form a5-methyleneoxazoline of formula (III) ##STR7##

(ii) chlorinating the 5-methyleneoxazoline of formula (III) in a solventusing trichloroisocyanuric acid to produce a chlorinated oxazolineintermediate of formula (IV) ##STR8## and

(iii) hydrolyzing the chlorinated oxazoline intermediate of formula (IV)with an aqueous acid to produce the desired monochloroketone of formula(I) ##STR9## wherein

Z is alkyl or substituted alkyl, aryl or substituted aryl, heteroaryl orsubstituted heteroaryl or phenylene,

R is a hydrogen atom or alkyl, and

R¹ and R² are each independently an alkyl or substituted alkyl group, orR¹ and R² together with the carbon atom to which they are attached forma cyclic structure.

In a preferred form of this embodiment,

Z is (C₁ -C₈)alkyl, phenyl or phenyl substituted with up to threesubstituents independently selected from the group consisting of halo,(C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₂ -C₆)alkynyl, nitro and cyano,2-naphthyl, 3-pyridyl and 1,4-phenylene,

R is a hydrogen atom or a (C₁ -C₄)alkyl, and

R¹ and R² are each independently a (C₁ -C₄)alkyl or R¹ and R² togetherwith the carbon atom to which they are attached form a cyclopentyl orcyclohexyl ring.

In a more preferred form of this embodiment,

Z is 3-heptyl, phenyl, 4-halophenyl, 2,6-dihalophenyl, 4-(C₁-C₄)alkylphenyl, 3,5-dihalophenyl, 3,5-di(C₁ -C₄)alkylphenyl, 4-(C₁-C₄)alkyl-3,5-dihalophenyl, 4-cyano-3,5-dihalophenyl, 4-(C₁-C₄)alkoxy-3,5-dihalophenyl, 4-nitrophenyl, 2-naphthyl, 3-pyridyl or1,4-phenylene,

R is a hydrogen atom, methyl or ethyl, and

R¹ and R² are each independently methyl or ethyl or R¹ and R² togetherwith the carbon atom to which they are attached form a cyclohexyl ring.

In an even more preferred form of this embodiment,

Z is 4-chlorophenyl, 2,6-difluorophenyl, 3,5-dimethylphenyl,3,5-dichloro-4-methylphenyl, 4-nitrophenyl, 1,4-phenylene, 2-naphthyl,3-pyridyl or 3-heptyl,

R is a hydrogen atom, and

R¹ and R² are each independently methyl or ethyl.

In both embodiments of this invention, the amount of TCIA which isemployed in step (ii) may be advantageously increased in order to form5-(dichloromethylene)oxazolines which are subsequently hydrolyzed toα,α-dichloroketones which are useful as fungicides. Specifically, thisfeature of this invention provides a process for the preparation of anα,α-dichloroketone compound of formula (IA) comprising the steps of

(i) cyclizing an alkynyl amide of formula (IIA) to form a5-methyleneoxazoline of formula (IIIA) ##STR10##

(ii) chlorinating the 5-methyleneoxazoline of formula (IIIA) in asolvent using trichloroisocyanuric acid to produce a dichlorinatedoxazoline intermediate of formula (IVA) ##STR11## and

(iii) hydrolyzing the dichlorinated oxazoline intermediate of formula(IVA) with an aqueous acid to produce the desired dichloroketone offormula (IA) ##STR12## wherein

Z is alkyl or substituted alkyl, aryl or substituted aryl, heteroaryl orsubstituted heteroaryl or phenylene, and

R¹ and R² are each independently an alkyl or substituted alkyl group, orR¹ and R² together with the carbon atom to which they are attached forma cyclic structure.

In a preferred form of this feature,

Z is (C₁ -C₈)alkyl, phenyl or phenyl substituted with up to threesubstituents independently selected from the group consisting of halo,(C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₂ -C₆)alkynyl, nitro and cyano,2-naphthyl, 3-pyridyl and 1,4-phenylene, and

R¹ and R² are each independently a (C₁ -C₄)alkyl or R¹ and R² togetherwith the carbon atom to which they are attached form a cyclopentyl orcyclohexyl ring.

In a more preferred form of this feature,

Z is 3-heptyl, phenyl, 4-halophenyl, 2,6-dihalophenyl, 4-(C₁-C₄)alkylphenyl, 3,5-dihalophenyl, 3,5-di(C₁ -C₄)alkylphenyl, 4-(C₁-C₄)alkyl-3,5-dihalophenyl, 4-cyano-3,5-dihalophenyl, 4-(C₁-C₄)alkoxy-3,5-dihalophenyl, 4-nitrophenyl, 2-naphthyl, 3-pyridyl or1,4-phenylene, and

R¹ and R² are each independently methyl or ethyl or R¹ and R² togetherwith the carbon atom to which they are attached form a cyclohexyl ring.

In an even more preferred form of this feature,

Z is 4-chlorophenyl, 2,6-difluorophenyl, 3,5-dimethylphenyl,3,5-dichloro-4-methylphenyl, 4-nitrophenyl, 1,4-phenylene, 2-naphthyl,3-pyridyl or 3-heptyl, and

R¹ and R² are each independently methyl or ethyl.

In this invention, alkyl means a (C₁ -C₈) straight or a (C₃ -C₈)branched chain alkyl group and includes, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-amyl,isoamyl, n-hexyl, isooctyl and the like. Substituted alkyl means analkyl substituted with one or more substituents selected from the groupconsisting of alkoxy, halo, alkylthio and cyano.

Alkoxy means a (C₁ -C₄) straight or a (C₃ -C₄) branched chain alkylgroup attached to an oxygen atom, for example, methoxy, ethoxy,isobutoxy and the like.

Alkylthio means a (C₁ -C₄) straight or a (C₃ -C₄) branched chain alkylgroup attached to an sulfur atom, for example, methylthio, n-propylthio,sec-butylthio and the like.

Halo means bromo, chloro, fluoro and iodo.

Aryl means phenyl, naphthyl, or phenyl or naphthyl substituted with oneto three substituents independently selected from the group consistingof halo, alkyl, alkynyl, alkoxy, nitro or cyano. Examples include, butare not limited to, phenyl, 2-naphthyl, 4-nitrophenyl, 4-chlorophenyl,3,5-dimethylphenyl, 2,6-difluorophenyl, 3,5-dichloro-4-methylphenyl,3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-dibromophenyl,3-chloro-4-ethyl-5-fluorophenyl, 3,5-dichloro-4-cyanophenyl,3,5-dichloro-4-methoxyphenyl, 3,5-difluoro-4-propargylphenyl,3,5-dibromo-4-methylphenyl and the like.

Alkynyl means a (C₂ -C₆)alkynyl, for example, ethynyl, propargyl,2-hexynyl and the like.

Heteroaryl means a 5-membered aromatic ring which may contain an oxygenatom, a sulfur atom, 1, 2 or 3 nitrogen atoms, an oxygen atom with 1 or2 nitrogen atoms or a sulfur atom with 1 or 2 nitrogen atoms, or a6-membered aromatic ring containing 1, 2 or 3 nitrogen atoms, orheteroaryl substituted with up to two substituents selected from halo,alkyl, haloalkyl or cyano. Examples include, but are not limited to2-furyl, 2-thienyl, 4-chloro-2-thienyl, 2-oxazolyl, 2-imidazolyl,1,2,4-triazol-1-yl, 2-imidazolyl, 2-pyrrolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 4-pyridazinyl, 4-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 4-chloro-3-pyridyl and the like.

Phenylene means 1,4-phenylene.

Although a specific isomer is shown throughout for the compound offormula (IV), it is to be understood that formula (IV) actuallyrepresents a mixture of the cis and trans isomeric forms.

In the first embodiment of this invention, the cyclization step (i) toform a ⁵ -methyleneoxazoline from an alkynyl amide is carried out usinga mild aqueous base in the presence of a phase transfer agent. Althoughthe phase transfer agent (PTA) is required, the choice of PTA which isemployed is not critical and may be non-ionic, cationic or amphoteric innature. Examples of the PTA include, but are not limited to, analkylphenoxy polyethoxy ethanol, a quaternary ammonium halide such astetrabutylammonium bromide, benzyltributylammonium chloride ortricaprylylmethylammonium chloride which is sold under the tradename ofAliquat® 336, and a quaternary phosphonium halide such as a (C₁₆-C₁₈)alkyltributylphosphonium bromide such as cetyltributylphosphoniumbromide. The amount of PTA employed is also not overly critical, but isgenerally in the range of from about 0.1% to about 25% by weight,preferably from about 0.1% to about 10% by weight, based on the alkynylamide starting material. The reaction temperature is usually from about25° C. up to the boiling point of the solvent/water system used. Apreferred condition is a reaction temperature of at least 50° C. up tothe boiling point of the solvent/water system used. Pressure is notimportant, but the reaction is usually run at atmospheric pressure forconvenience. The time of the reaction will depend upon the temperatureemployed, the substituent pattern of the starting alkynyl amide, thesolvent utilized, the nature of the base and the PTA, and the size anddesign of the reactor. However, the reaction is usually convenientlyeffected in a time of 24 hours or less and more usually 10 hours orless.

Most common aqueous bases can be used for the formation of the oxazolinefrom the alkynyl amide. A basic ion exchange resin may also be used.Preferred bases are sodium hydroxide (NaOH) and potassium hydroxide(KOH) or mixtures thereof, sodium carbonate (Na₂ CO₃) and potassiumcarbonate (K₂ CO₃) or mixtures thereof, and sodium bicarbonate (NaHCO₃)and potassium bicarbonate (KHCO₃) or mixtures thereof. More preferredare NaOH, KOH, NaHCO3 and Na2CO₃. Even more preferred is NaOH. Varioussolvents can be used in this reaction. They can be either non-polar, forexample an aliphatic hydrocarbon such as heptane and isooctane or anaromatic hydrocarbon such as toluene and a xylene, or polar, for examplean ether. Generally, the hydroxide type bases are best used in anon-polar solvent in order to avoid side reactions. The bicarbonate andcarbonate type bases can be used with either type solvent, but areusually advantageously employed with the polar types. The amount of baseemployed is usually at least 0.05 equivalent per equivalent of alkynylamide. A preferred amount is at least 0.1 equivalent of base. A morepreferred amount is at least 0.25 equivalent of base.

In a typical representative reaction procedure for this first embodimentfor step (i), the alkynyl amide, solvent, base and phase transfer agentare added together and heated at reflux until no starting material couldbe detected by gas chromatographic (GC) analysis. After cooling, thelower aqueous layer is discarded and the organic solution is washed withbrine, dried over a desiccant, and filtered. If desired, the filtratecan be further treated with decolorizing charcoal and refiltered. Thesolution is concentrated to remove most of the solvent and the resultingclear oil distilled under vacuum to afford the 5-methyleneoxazolinematerial.

In the second embodiment of this invention, the cyclization step (i) toform a 5-methyleneoxazoline from an alkynyl amide is carried out usingan acid, preferably an anhydrous acid, in the presence of an organicsolvent. The acid may be either a mineral or an organic acid. Examplesof the acid include, but are not limited to, oleum, methanesulfonicacid, toluenesulfonic acid, trifluoroacetic acid and trichloroaceticacid. Preferred acids are methanesulfonic acid and trichloroacetic acid.A more preferred acid is methanesulfonic acid. The amount of acidemployed can vary, but an amount of from about 5 mole percent to about200 mole percent, based on the starting substituted amide material, isgenerally used. A preferred amount is from about 5 mole percent to about100 mole percent. A more preferred amount is from about 5 mole percentto about 20 mole percent. The solvent employed can be either a polar ornon-polar solvent and is preferably anhydrous in nature. Examples ofpolar solvents include, but are not limited to, esters such as ethylacetate and butyl acetate, ethers such as methyl tert-butyl ether, andnitriles such as acetonitrile. Examples of non-polar solvents include,but are not limited to, aliphatic hydrocarbons such as heptane, aromatichydrocarbons such as toluene, and haloaromatic hydrocarbons such aschlorobenzene. Preferred solvents are butyl acetate, chlorobenzene andheptane. The reaction temperature is usually from about 20° C. to thereflux temperature of the solvent system employed. A preferredtemperature is from about 25° C. to about 130° C. A more preferredtemperature is from about 80° C. to about 120° C. Pressure is notimportant, but the reaction is usually run at atmospheric pressure forconvenience. The time of the reaction will depend upon the temperatureemployed, the substituent pattern of the starting alkynyl amide, thesolvent utilized, the nature of the acid, and the size and design of thereactor. However, the reaction is usually conveniently effected in atime of from about 2 hours to about 5 days and more usually 3 days orless.

In a typical representative reaction procedure for step (i) of thissecond embodiment, the starting amide is added to the reaction solventfollowed by the catalyst. The reaction is then brought to temperatureand stirred until complete, cooled to ambient temperature and quenchedwith saturated sodium bicarbonate. The layers are separated, aqueousextracted, organics combined, dried, filtered and evaporated to drynessto give the desired product.

In both the embodiments of this invention, the chlorination step (ii) ofthe 5-methyleneoxazoline using TCIA may be performed at a temperature offrom about -30° to about 100° C. A preferred chlorination temperature isfrom about 0° to 70° C. More preferred in order to obtain the bestchlorination selectivity is a temperature of about 50° C. or lower. Evenmore preferred is a temperature from 0° to 30° C. The reaction is notpressure-dependent, but a pressure of 1 atmosphere is usually preferredfor convenience. The stoichiometry of the reagents is extremelyimportant. If less than 0.333 equivalent of TCIA per equivalent of5-metllyleneoxazoline is used, some of the 5-methyleneoxazoline startingmaterial will remain unreacted. If greater than 0.333 equivalent isused, an overchlorinated intermediate is formed that leads to adichloroketone after hydrolysis. However, as noted previously, an addedfeature of this invention provides for the convenient formation of a5-(dichloromethylene)oxazoline and subsequent formation in step (iii) ofan α,α-dichloroketone when ≧0.667 equivalent of TCIA is used perequivalent of the 5-methyleneoxazoline in the situation where themethylene group of the oxazoline is not substituted with an alkyl group.The chlorination reaction time can vary from about 5 minutes to about 1hour and is dependent on both the size and type of reactor equipmentemployed and the solvent used. The chlorination solvent is usually apolar solvent such as, but not limited to, an ether, an ester or aketone, for example ethyl acetate, butyl acetate and methyl t-butylether. Preferred solvents are ethyl acetate or butyl acetate. Nonpolarsolvents such as an aromatic hydrocarbon, for example toluene, or analiphatic hydrocarbon, for example heptane and isooctane, may be alsoemployed when admixed with a miscible polar type solvent or when heatedto a temperature of about 40° C. After the chlorination reaction iscarried out to the desired stage, the cyanuric acid by-product may beremoved by filtration and/or by washing with a common base such assodium carbonate, sodium hydroxide and the like. The resulting solutioncontaining the 5-chlorometlhyleneoxazoline is then subjected to thehydrolysis step (iii).

In the hydrolysis step (iii), a temperature of about 50° C. or higher isrequired. Preferably, the hydrolysis is performed from about 50° to 100°C. More preferably, the temperature employed is from about 50° to 80° C.Either an aqueous acid or a non-aqueous acid admixed with some water maybe employed. A common acid such as, but not limited to, hydrochloricacid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid ortoluenesulfonic acid is convenient to use. Aqueous hydrochloric acid orsulfuric acid are preferred. An acidic ion-exchange resin may also beutilized. When hydrochloric acid or sulfuric acid are used, additionalwater is usually added to facilitate the hydrolysis. It is preferredthat about 0.05 to 0.5 equivalent of an aqueous acid is used perequivalent of 5-chloromethyleneoxazoline. More preferred is the use ofabout 0.1 to 0.25 equivalent of aqueous hydrochloric acid per equivalentof 5-chloromethyleneoxazoline. The hydrolysis step usually takes fromabout 3 to about 24 hours, with the time depending on the nature of theZ group, the temperature and the size and nature of the equipmentemployed. The pressure used is not critical. However, 1 atmosphere isusually preferred for convenience.

In a typical representative reaction procedure for steps (ii) and (iii)of both embodiments, the oxazoline and solvent are combined and theresulting solution is chilled to 0-5° C. using an ice bath. The TCIA isadded gradually, keeping the reaction temperature below 30° C. ifpossible. Once the TCIA has been added, the resulting slurry is warmedto room temperature and stirred until the reaction is complete based ongas chromatographic (GC) analysis. The cyanuric acid by-product isremoved by filtration and the solution is then washed with anappropriate base such as a sodium bicarbonate or sodium hydroxidesolution to remove any remaining cyanuric acid. The solution containingthe 5-chloromethyleneoxazoline is returned to the flask and heated to60° C. Concentrated hydrochloric acid and water are added and thesolution is stirred until the hydrolysis is complete. The reactionmixture is cooled to room temperature and the desired α-chloroketonecrystallizes on cooling. The solid obtained is filtered, washed anddried to give the product. A second crop is frequently obtained byconcentration and cooling of the filtrate solution.

The following examples, tables and experimental procedures are providedfor guidance to the practitioner and are not meant to limit the scope ofthe invention which is defined by the claims.

                                      TABLE I    __________________________________________________________________________    EXAMPLES B1 TO B14    Base Catalyzed Formation of 5-Methyleneoxazolines from    Alkynyl Amides in the Presence of a Phase Transfer Agent (PTA)    1 #STR13##    Example                        bp °C.,    No. B         Z         R.sup.1                        R.sup.2                             Yield (%)                                   (mm Hg)    __________________________________________________________________________    1, 2, 3         phenyl    CH.sub.3                        CH.sub.3                             95, 98, 92                                   70-75 (0.6)    4, 5 3,5-dimethylphenyl                   CH.sub.3                        CH.sub.3                             98, 98                                   86-94 (0.4)     6   4-chlorophenyl                   CH.sub.3                        C.sub.2 H.sub.5                             97    95 (0.6)     7   2,6-difluorophenyl                   CH.sub.3                        CH.sub.3                             95    80 (1.0)     8   2,6-difluorophenyl                   --(CH.sub.2).sub.5--                             96    110-112 (0.5)     9   3,5-dichloro-4-                   CH.sub.3                        C.sub.2 H.sub.5                             87    128 (1.0)         methylphenyl    10   4-nitrophenyl                   CH.sub.3                        CH.sub.3                             90    mp 91-94    11   1,4-phenylene                   C.sub.2 H.sub.5                        C.sub.2 H.sub.5                             87    mp 143-144    12   2-naphthyl                   CH.sub.3                        CH.sub.3                             95    132-137 (0.5)    13   3-pyridyl CH.sub.3                        CH.sub.3                             96    80-87 (0.6)    14   heptan-3-yl                   CH.sub.3                        CH.sub.3                             98    62 (1.0)    __________________________________________________________________________

Example B1: Preparation of 4,4-dimethyl-5-methylene-2-phenyloxazoline

To a round bottom flask equipped with a magnetic stir bar, heatingmantle, and reflux condenser was added N-(3-methylbutyn-3-yl)benzamide(25.00 g, 133.5 mmol), 200 mL of toluene, 27 mL of 0.5N aqueous sodiumhydroxide, and 2.00 g (4.95 mmol, 3.7 mol %) of Aliquat® 336. Theresulting mixture was heated at reflux for 3 h at which time no startingmaterial could be detected by gas chromatographic (GC) analysis. Aftercooling, the mixture was transferred to a separators funnel. The loweraqueous layer was discarded. The organic solution was washed with brine,dried over MgSO₄, and filtered. The filtrate was treated with 2.0 g ofdecolorizing charcoal and filtered again. The solution was concentratedusing a rotary evaporator to afford 26.41 g of a clear oil. The productwas distilled under vacuum (70-75° C., 0.6 mm Hg) to afford 23.65 (95%yield) of a clear colorless liquid. This material,4,4-dimethyl-5-methylene-2-phenyloxazoline, was found to be a singlecomponent by gas chromatographic analysis: ¹ H NMR (400 MHz, CDCl₃) δ7.99 (d, J=6.7 Hz, 2H), 7.50-7.35 (m, 3H), 4.73 (d, J=2.8 Hz, 1H), 4.23(d, J=2.8 Hz, 1H), 1.45 (s, 6H); ¹³ C NMR (100 MHz, CDCl₃) δ 167.8,159.8, 131.6, 128.4, 126.0, 126.95, 82.3, 69.0, 29.7.

Example B2: Preparation of 4,4-dimethyl-5-methylene-2-phenyloxazoline

In a manner similar to example 1, a 98% yield of4,4-dimethyl-5-methylene-2-phenyloxazoline was obtained using methyltert-butyl ether in place of toluene, and a reaction time of 4 h.

Example B3: Preparation of 4,4-dimethyl-5-methylene-2-phenyloxazoline

In a manner similar to example 1, a 92% yield of4,4-dimethyl-5-methylene-2-phenyloxazoline was obtained usingchlorobenzene in place of toluene, and a reaction time of 2.5 h.

Example B4: Preparation of2-(3,5-dimethylphenyl)-4,4-dimethyl-5-methyleneoxazoline

To a round bottom flask equipped with a magnetic stir bar, heatingmantle, and reflux condenser was addedN-(3-methylbutyn-3-yl)-3,5-dimethylbenzamide (25.00 g, 116.1 mmol), 200mL of toluene, 50 mL of 0.5N aqueous sodium hydroxide, and 1.74 g (4.31mmol, 3.7 mol %) of Aliquat® 336. The resulting mixture was heated atreflux for 1.5 h. After cooling, the mixture was transferred to aseparatory funnel. The lower aqueous layer was discarded. The organicsolution was washed with brine, dried over MgSO₄, and filtered. Thesolution was concentrated using a rotary, evaporator to afford a clearcolorless oil which was distilled (86-94° C., 0.4 mm) to give 24.43 g(98%) of 2-(3,5-dimethylphenyl)-4,4-dimethyl-5-methyleneoxazoline as acolorless liquid: ¹ H NMR (400 MHz, CDCl₃) δ 7.62 (s, 2H), 7.09 (s, 1H),4.73 (d, J=3.2 Hz, 1H), 4.22 (d, J=3.2 Hz, 1H), 2.30 (s, 6H), 1.44 (s,6H); ¹³ C NMR (100 MHz, CDCl₃) δ 167.9, 160.1, 138.1, 133.3, 126.7,125.8, 82.1, 68.9, 29.8, 21.1.

Example B5: Preparation of2-(3,5-dimethylphenyl)-4,4-dimethyl-5-methyleneoxazoline

In a manner similar to example 4, a 98% yield of2-(3,5-dimethylphenyl)-4,4-dimethyl-5-methyleneoxazoline-was obtainedusing isooctane as the solvent, 2.95 g of hexadecyltributylphosphoniumbromide as the phase transfer catalyst, and a reaction time of 2 h.

Example B6: Preparation of2-(4-chlorophenyl)-4-ethyl-4-methyl-5-methyleneoxazoline

In a manner similar to example 4, a 97% yield of2-(4-chlorophenyl)-4-ethyl4-methyl-5-methyleneoxazoline was obtainedusing isooctane as the solvent, 2.84 g of octadecyltributylphosphoniumbromide as the phase transfer catalyst, and a reaction time of 1.5 h: bp(95° C., 0.6 mm); mp 55-57° C.; ¹ H NMR (400 MHz, CDCl₃) δ 7.92 (d,J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 4.80 (d, J=2.4 Hz, 1H), 4.19 (d,J=2.4 Hz, 1H), 1.86 (dt, J=20.8, 7.5 Hz, 1H), 1.60 (dt, J=20.8, 7.5 Hz,1H), 1.42 (s, 3H), 0.80 (t, J=7.5 Hz, 3H); ¹³ C NMR (100 MHz, CDCl₃) δ166.0, 159.0, 137.8, 129.4, 128.7, 125.4, 83.1, 72.9, 35.0, 28.6, 8.3.

Example B7: Preparation of2-(2,6-difluorophenyl)-4,4-dimethyl-5-methyleneoxazoline

In a manner similar to example 4, a 95% yield of2-(2,6-difluorophenyl)4,4-dimethyl-5-methyleneoxazoline was obtainedusing isooctane as the solvent, 2.26 g of Aliquat® 336 as the phasetransfer catalyst, and a reaction time of 1.25 h: bp (80° C., 1.0 mm); ¹H NMR (400 MHz, CDCl₃) δ 7.42 (tt, J=8.0, 6.0 Hz, 1H), 6.98 (t, J=8.0Hz, 2H), 4.74 (d, J=3.2 Hz, 1H), 4.30 (d, J=3.2 Hz, 1H), 1.45 (s, 6H);¹³ C NMR (100 MHz, CDCl₃) δ 167.1, 161.2 (dd, J=256.7, 5.7 Hz), 152.6,132.8 (t, J=10.3 Hz), 112.0 (d, J=20.0 Hz), 106.7 (t, J=17.1 Hz), 83.0,69.4, 29.6.

Example B8: Preparation of2-(2,6-difluorophenyl)-5-methylene-4,4-(pentamethylene)oxazoline

In a manner similar to example 4, a 96% yield of2-(2,6-difluorophenyl)-5-methylene-4,4-(pentamethylene)oxazoline wasobtained using toluene as the solvent, 2.41 g ofhexadecyltributylphosphonium bromide as the phase transfer catalyst, anda reaction time of 6 h: bp (110-112° C., 0.5 mm); mp 43-46° C.; ¹ H NMR(400 MHz, CDCl₃) δ 7.38 (tt, J=8.4, 6.0 Hz, 1H), 6.94 (t, J=8.8 Hz, 2H),4.72 (d, J=3.2 Hz, 1H), 4.26 (d, J=3.2 Hz, 1H), 2.0-1.3 (m, 10H); ¹³ CNMR (100 MHz, CDCl₃) δ 167.6, 161.2 (dd, J=256.3, 6.0 Hz), 151.9, 132.6(t, J=10.3 Hz), 111.9 (dd, J=20.2, 5.4 Hz), 107.2 (t, J=18.3 Hz), 83.2,72.6, 39.3, 25.6, 22.2.

Example B9: Preparation of2-(3,5-dichloro-4-methylphenyl)-4-ethyl-4methyl-5-methyleneoxazoline

In a manner similar to example 4, a 87% yield of2-(3,5-dichloro-4-methylphenyl)-4-ethyl-4-methyl-5-methyleneoxazolinewas obtained using heptane as the solvent, 1.08 g of Aliquat® 336 as thephase transfer catalyst, a solution of 10.2 g sodium carbonate in 80 mLwater, and a reaction time of 1.5 h: bp (128° C., 1.0 mm); ¹³ C NMR (100MHz, DMSO-d₆) δ 165.1, 156.5, 137.6, 135.0, 126.5, 126.0, 83.9, 72.7,34.0, 28.0, 17.4, 8.1.

Example B10: Preparation of2-(4-nitrophenyl)4,4-dimethyl-5-methyleneoxazoline

In a manner similar to example 4, a 90% yield of2-(4-nitrophenyl)4,4-dimethyl-5-methyleneoxazoline was obtained usingisooctane as the solvent, 2.25 g of Aliquat® 336 as the phase transfercatalyst, and a reaction time of 1.25 h. The crude product wasrecrystallized from hexane to give 22.61 g of a light orange solid: mp91-94° C.; ¹ H NMR (400 MHz, CDCl₃) δ 8.29 (d, J=8.8 Hz, 2H), 8.16 (d, J=8.8 Hz, 2H), 4.80 (d, J=3.2 Hz, 1H), 4.33 (d, J=3.2 Hz, 1H), 1.48 (s,6H); ¹³ C NMR (100 MHz, CDCl₃) δ 167.3, 158.1, 149.6, 132.8, 129.1,123.6, 83.5, 69.7, 29.6.

Example B11: Preparation ofbis(4,4-diethyl-5-methyleneoxazolin-2-yl)-1,4-phenylene

In a manner similar to example 4, a 87% yield ofbis(4,4-diethyl-5-methyleneoxazolin-2-yl)-1,4-phenylene was obtainedusing toluene as the solvent, 2.00 g of Aliquat® 336 as the phasetransfer catalyst, 50 mL of 1N NaOH solution, and a reaction time of 2h. The crude product was recrystallized from hexane to give 21.81 g of awhite solid: mp 143-144° C.; ¹ H NMR (400 MHz, CDCl₃) δ 8.09 (s, 4H),4.90 (d, J=3.2 Hz, 2H), 4.17 (d, J =3.2 Hz, 2H), 1.92 (dt, J=21.2, 7.4Hz, 4H), 1.58 (dt, J=21.2, 7.4 Hz, 4H), 8.81 (t, J=7.4Hz, 12H); ¹³ C NMR(100 MHz, CDCl₃) δ 164.0, 159.5, 129.6, 128.2, 83.6, 77.2, 34.0, 8.1.

Example B12: Preparation of4,4-dimethyl-5-methylene-2-(2-naphthyl)oxazoline

In a manner similar to example 4, a 95 % yield of4,4-dimethyl-5-methylene-2-(2-naphthyl)oxazoline was obtained usingtoluene as the solvent, 1.00 g of Aliquat® 336 as the phase transfercatalyst, 50 mL of 1N NaOH solution, and a reaction time of 1.5 h: bp(132-137° C., 0.5 mm); ¹ H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 8.04(dd, J=8.8, 2.0 Hz, 1H), 7.84 (dd, J=6.4, 2.4 Hz, 1H), 7.79 (d, J=8.4Hz, 1H), 7.75 (dd, J=6.8, 2.8 Hz, 1H), 7.48-7.40 (m, 2H), 4.78 (d, J=2.8Hz, 1H), 4.25 (d, J=2.8Hz, 1H), 1.48 (s, 6H); ¹³ C NMR (100 MHz, CDCl₃)δ 167.8, 159.9, 134.7, 132.6, 128.8, 128.7, 128.2, 127.7, 127.6, 126.5,124.3, 124.1, 82.3, 69.1, 29.8.

Example B13: Preparation of4,4-dimethyl-5-methylene-2-(3-pyridyl)oxazoline

In a manner similar to example 4, a 96% yield of4,4-dimethyl-5-methylene-2-(3-pyridyl)oxazoline was obtained usingisooctane as the solvent, 2.00 g of stearyltributylphosphonium bromideas the phase transfer catalyst, 50 mL of 0.5N NaOH solution, and areaction time of 1 h: bp 80-87° C. (0.6 mm); ¹³ C NMR (100 MHz, CDCl₃) δ164.9, 152.0, 148.0, 135.2, 123.4, 86.8, 69.7, 48.2, 29.0.

Example B14. Preparation of2-heptan-3-yl-4,4-dimethyl-5-methyleneoxazoline

In a manner similar to example 4, a 98% yield of2-heptan-3-yl-4,4-dimethyl-5-methyleneoxazoline was obtained usingheptane as the solvent, 4.81 g of Aliquat® 336 as the phase transfercatalyst, KOH instead of NaOH, and a reaction time of 2 h: bp (62° C.,1.0 mm); ¹³ C NMR (100 MHz, CDCl₃) δ 168.2,165.8, 81.4, 68.1, 41.0,31.8, 29.8, 29.5, 25.4, 22.6, 14.0, 11.7.

Comparative Examples: Base Catalyzed Cyclization without the Presence ofa PTA

To further demonstrate the utility of the present invention whereby the5-methyleneoxazoline is formed from a substituted amide using a base inthe presence of a PTA, the following comparative examples were performedwithout a PTA being present.

Comparative Example B-1

When an experiment was run in a manner similar to example B4 but in theabsence of any phase-transfer catalyst, only 21% of2-(3,5-dimethylphenyl)4,4-dimethyl-5-methyleneoxazoline was obtainedusing heptane as the solvent and a reaction time of 8 h. The other 79%of the recovered material consisted of unreactedN-(3-methylbutyn-3-yl)-3,5-dimethylbenzamide.

Comparative Example B-2

When an experiment was run in a manner similar to example B4 usingtoluene as solvent but in the absence of any phase-transfer catalyst,N-(3-methylpentyn-3-yl)-3,5-dichloro-4-methylbenzamide was recoveredunchanged after a reaction time of 8 h.

The following procedure for the acid catalyzed formation of the5-methyleneoxazoline from a substituted amide was utilized for allexamples A1 to A18 shown in Table II:

To 2 g of aminoalkyne in 10 mL of solvent was added from 5 to 200 mol %of acid catalyst. The mixture was then heated to the desiredtemperature. Anhydrous starting materials are used. The reaction wasstirred until GC analysis indicated starting material had been consumedor the reaction was no longer consuming starting material. It was thencooled to room temperature where it was quenched with 15 mL of saturatedaqueous sodium bicarbonate solution and the layers separated. Theaqueous layer was extracted with ethyl acetate (15 mL), the organicswere combined, dried over sodium sulfate, filtered and evaporated todryness in vacuo to give the desired product in the yield shown in TableII. Products were identified by comparison to known standards and by ¹ HNMR spectroscopy.

TABLE II: EXAMPLES A1 to A18 (following page) ##STR14##

In Table II, weight yield refers to the aggregate of the desired5-methyleneoxazoline product, a ketone having the formula ##STR15## andthe substituted amide starting material.

Examples C1-C11 illustrate the experimental conditions utilized in thepreparation of the desired α-monochloroketones from the5-methyleneoxazoline, prepared by either the base catalyzed cyclizationin the presence of a PTA or the acid catalyzed cyclization of thesubstituted amide starting material, using TCIA and followed byhydrolysis using aqueous acid.

                                      TABLE II    __________________________________________________________________________    Acid Catalyzed Formation of 5-Methyleneoxazolines from Acetylenic Amides    Example           Acid (amount  React.                                        Reaction       %   %   %    A    Z      R.sup.1                   R.sup.2                      in mol %)                              Solvent                                    Time                                        Temperature                                               Weight Yield                                                       Product                                                           Ketone                                                               amide    __________________________________________________________________________     1   3,5-dichloro-4-                CH.sub.3                   C.sub.2 H.sub.5                      p-toluenesulfonic                              ethyl acetate                                    6 h reflux 90% by GC                                                       72  18.8                                                               0         methylphenyl acid (5%)     2   3,5-dichloro-4-                CH.sub.3                   C.sub.2 H.sub.5                      CH.sub.3 CO.sub.2 H                              butyl acetate                                    3 d reflux 87% by GC                                                       71  0   16         methylphenyl (150%)     3   3,5-dichloro-4-                CH.sub.3                   C.sub.2 H.sub.5                      F.sub.3 CCO.sub.2 H (5%)                              butyl acetate                                    2 d 20° C.-reflux                                               92.4%                                                   by GC                                                       81  5   7         methylphenyl     4   3,5-dichloro-4-                CH.sub.3                   C.sub.2 H.sub.5                      Oleum (5%)                              butyl acetate                                    6 h 20-25° C.                                               90.6%                                                   by GC                                                       70  6.6 14         methylphenyl     5   3,5-dichloro-4-                CH.sub.3                   C.sub.2 H.sub.5                      CH.sub.3 SO.sub.3 H (5%)                              butyl acetate                                    5 h reflux 93% by GC                                                       71  22  0         methylphenyl     6   3,5-dichloro-4-                CH.sub.3                   C.sub.2 H.sub.5                      CH.sub.3 SO.sub.3 H (5%)                              butyl 2 d reflux 80% by GC                                                       67  13  0         methylphenyl         acetate.sup.(a)     7   3,5-dichloro-4-                CH.sub.3                   C.sub.2 H.sub.5                      CH.sub.3 SO.sub.3 H (5%)                              butyl 5 h reflux 92.8%                                                   by GC                                                       89  3.8 0         methylphenyl         acetate.sup.(b)     8   3,5-dichloro-4-                CH.sub.3                   C.sub.2 H.sub.5                      p-toluenesulfonic                              butyl acetate/                                    2 d reflux 90.5%                                                   by GC                                                       87  3.5 0         methylphenyl acid (5%)                              acetic                              anhydride                              (2:1)     9   4-nitrophenyl                CH.sub.3                   CH.sub.3                      CH.sub.3 SO.sub.3 H (10%)                              butyl acetate                                    15-18 h                                        80° C.                                               92% isolated                                                       88  9.2 0    10   4-nitrophenyl                CH.sub.3                   CH.sub.3                      CH.sub.3 SO.sub.3 H (5%)                              heptane                                    3 h 90° C.                                               95.6%                                                   isolated                                                       99.3                                                           0.7 0    11   4-nitrophenyl                CH.sub.3                   CH.sub.3                      CH.sub.3 SO.sub.3 H (5%)                              acetonitrile                                    2 d reflux 99.7%                                                   by GC                                                       81  17  1.7    12   4-nitrophenyl                CH.sub.3                   CH.sub.3                      CH.sub.3 SO.sub.3 H (5%)                              toluene                                    3 h reflux 91.6%                                                   isolated                                                       98  2   0    13   4-nitrophenyl                CH.sub.3                   CH.sub.3                      CH.sub.3 SO.sub.3 H (5%)                              chloro-                                    2 h 90° C.                                               83% isolated                                                       100 0   0                              benzene    14   4-nitrophenyl                CH.sub.3                   CH.sub.3                      Cl.sub.3 CCO.sub.2 H (2 eq)                              butyl acetate                                    4 h 90° C.                                               99% isolated                                                       89  9   0    15   2-heptyl                CH.sub.3                   CH.sub.3                      Cl.sub.3 CCO.sub.2 H                              heptane                                    4 h reflux 90% isolated                                                       100 0   0                      (200%)    16   2-heptyl                CH.sub.3                   CH.sub.3                      CH.sub.3 SO.sub.3 H (5%)                              heptane                                    3 h reflux 93.5%                                                   isolated                                                       98.8                                                           0   1    17   3,5-Dimethyl-                CH.sub.3                   CH.sub.3                      CH.sub.3 SO.sub.3 H (5%)                              heptane                                    2 h 85-90° C.                                               94.8%                                                   isolated                                                       100 0   0         phenyl    18   3,5-Difluoro-                CH.sub.3                   CH.sub.3                      Cl.sub.3 CCO.sub.2 H                              t-butyl                                    5 d 50° C.                                               97% isolated                                                       94.3                                                           5.7 0         phenyl       (100%)  methyl ether    __________________________________________________________________________     .sup.(a) 2 equivalents of butyl acetate added at the beginning of the     reaction.     .sup.(b) 0.5 equivalent of acetic anhydride added at the beginning of the     reaction.

Example C1: Preparation ofN-(1-chloro-3-methyl-2-oxobut-3-yl)-4-nitrobenzamide

A solution of 4,4-dimethyl-5-methylene-2-(4-nitrophenyl)oxazoline (10.0g, 43.1 mmol) and ethyl acetate (35 mL) was cooled to 5° C. using an icebath. Trichloroisocyanuric acid (3.33 g, 14.3 mmol) was added in severalportions over 15 minutes in order to keep the reaction temperature below40° C. When the addition was complete the reaction mixture was cooled to20° C., and the ice bath was removed. The reaction was monitored by GCanalysis for disappearance of the starting material. After 1.5 h, anadditional 0.25 g (1.07 mmol) of the chlorinating agent was added inorder to complete the chlorination. When the reaction was complete, themixture was filtered. The filtrate was washed with ethyl acetate (15mL). The filtrate was transferred to a round-bottom flask and heated to60° C.; hydrochloric acid (0.85 g of a 37% solution) and water (2.8 mL)were added. The reaction mixture was stirred at 60° C. for 5 h, thencooled to room temperature. The resulting slurry was stored in arefrigerator overnight. The mixture was filtered, and the solids wererinsed with cold filtrate solution. The filtrate was concentrated toapproximately half of its original volume by evaporation under reducedpressure. Hexane was gradually added until the solution clouded; theflask was chilled in a refrigerator at 8° C. overnight, then the slurrywas filtered to obtain a second crop of crystals. Both crops were driedat 60° C. under vacuum, yieldingN-(1-chloro-3-methyl-2-oxobut-3-yl)-4-nitrobenzamide (10.78 g, 88%) as awhite solid, (mp 181-182° C.).

By following substantially the same procedure, the compounds of ExamplesC2-C11 were prepared as shown in Table III.

                                      TABLE III    __________________________________________________________________________    Preparation of α-Chloroketones from a    5-Methyleneoxazoline and TCIA, Followed by Hydrolysis    2 #STR16##    3 #STR17##    Example                     Product    No. C Z         R.sup.1                          R.sup.2                                Yield (%)                                       mp (°C.)    __________________________________________________________________________    1     4-nitrophenyl                    CH.sub.3                          CH.sub.3                                88     181-182    2     4-chlorophenyl                    CH.sub.2 CH.sub.3                          CH.sub.3                                76     113-114    3     3,5-dimethylphenyl                    CH.sub.3                          CH.sub.3                                75     162-164    4     2,6-difluorophenyl                    CH.sub.3                          CH.sub.3                                75     191-192    5     2,6-difluorophenyl                    --(CH.sub.2).sub.5--                                74     171-172    6     3,5-dichloro-4-                    CH.sub.2 CH.sub.3                          CH.sub.3                                87     157-158          methylphenyl    7     phenyl    CH.sub.3                          CH.sub.3                                74     154-155    8     1-ethylpentyl                    CH.sub.3                          CH.sub.3                                58     58-60    9     2-naphthyl                    CH.sub.3                          CH.sub.3                                60     151-152    10    3-pyridyl CH.sub.3                          CH.sub.3                                85     128 (decomp.)    11    1,4-phenylene                    CH.sub.2 CH.sub.3                          CH.sub.2 CH.sub.3                                60     193-196    __________________________________________________________________________

To further illustrate the benefits of the present invention by usingTCIA as a chlorinating agent for 5-methyleneoxazolines, the followingcomparative examples were performed with other conventional chlorinatingagents.

Comparative example C-1: Use of Chlorine Gas

A solution of2-(3,5-dichloro-4-methylphenyl)-4-ethyl-4-methyl-5-methyleneoxazoline(20.0 g, 70.4 mmol) and methanol (100 mL) was cooled to 0° C. Chlorinegas was bubbled into the solution; the reaction was monitored by gaschromatography..sup.(1) The chlorine feed was halted when the startingmaterial disappeared (1.5 h). The solution was purged with nitrogen toremove any remaining chlorine, then the solution was heated to 50° C.Water (20 mL) was added, and the reaction was stirred until hydrolysiswas complete. The reaction mixture was cooled to room temperature, andthe slurry was filtered. The wetcake was washed with cold solution of10% water in methanol and dried in a vacuum oven to yield 15.89 g ofwhite solid. The product contained 71%N-(1-chloro-3-methyl-2-oxopent-3-yl)-3,5-dichloro-4-methylbenzamide, 16%N-(1,1-dichloro-3-methyl-2-oxopent-3-yl)-3,5-dichloro-4-methylbenzamide,and 0.8% N-(3-methyl-2-oxopent-3-yl)-3,5-dichloro-4-methylbenzamide. Theyield of the desired monochloroketone was estimated at 48%. (Compare toExample C6).

Comparative Example C-2: Use of N-Chlorosuccinimide

A solution of2-(3,5-dichloro-4-methylphenyl)-4-ethyl-4-methyl-5-methyleneoxazoline(5.0 g, 17.6 mmol) and ethyl acetate (20 mL) was treated withN-chlorosuccinimide (2.35 g, 17.6 mmol). The solution was stirred atambient temperature for 70 h. The reaction mixture contained 50%unreacted starting material and 50% of the desired5-chloromethylene-2-(3,5-dichloro-4-methylphenyl)4-ethyl-4-methyloxazoline.(Compare to Example C6).

It is to be understood that changes and variations in this invention maybe made without departing from the spirit and scope of this invention asdefined by the appended claims.

We claim:
 1. A method of preparing a 5-(chloromethylene)oxazoline offormula (IV) by chlorinating the 5-(chloromethylene)oxazoline of formula(III) in a solvent using trichloroisocyanuric acid ##STR18## wherein Zis phenyl or phenyl substituted with up to three substituentsindependently selected from the group consisting of halo, (C1-C4)alkyl,(C1-C4)alkoxy, (C2-C6)alkynyl, nitro and cyano, 3-pyridyl,R1 and R2 areeach independently a (C1-C4)alkyl or R1 and R2 together with the carbonatom which they are attached form a cyclopentyl or cyclohexyl ring.